1. Field of the Invention
The present invention relates to a pharmaceutical composition and a method for inhibiting angiogenesis comprising administering a N-Acetylated Alpha-Linked Acidic Dipeptidase (NAALADase) inhibitor to a patient in need thereof.
2. Description of Prior Art
The term xe2x80x9cangiogenesisxe2x80x9d describes the process whereby new capillaries are formed.
Angiogenesis is essential for normal physiological processes, such as growth, fertility and soft tissue wound healing. However, a significant percentage of all diseases are also dependent upon angiogenesis.
Cancer, for example, is an angiogenesis-dependent disease. Cancer tumor cells secrete or release angiogenic substances that activate nearby endothelial cells. These endothelial cells respond by expressing a cell autonomous pattern of behavior that culminates in the formation of new blood vessels. Research during the last three decades has demonstrated that angiogenesis is necessary to sustain the growth, invasion and metastasis of cancer tumors.
In addition to cancer, ailments such as rheumatoid arthritis, cardiovascular disease, neovascular diseases of the eye, peripheral vascular disorders, and dermatologic ulcers are dependent upon angiogenesis.
Research has shown that inhibiting angiogenesis offers a treatment that is complementary to, or an alternative to, traditional anti-angiogenic treatment options, such as surgical, chemo- and radiation therapies.
NAALADase Inhibitors
NAAG and NAALADase have been implicated in several human and animal pathological conditions relating to glutamate abnormalities and neurotoxicity. For example, it has been demonstrated that intra-hippocampal injections of NAAG elicit prolonged seizure activity. More recently, it was reported that rats genetically prone to epileptic seizures have a persistent increase in their basal level of NAALADase activity. These observations lend support to the hypothesis that increased availability of synaptic glutamate elevates seizure susceptibility, and suggest that NAALADase inhibitors may provide anti-epileptic activity.
NAAG and NAALADase have also been implicated in the pathogenesis of ALS and in the pathologically similar animal disease called Hereditary Canine Spinal Muscular Atrophy (HCSMA). It has been shown that concentrations of NAAG and its metabolitesxe2x80x94NAA, glutamate and aspartatexe2x80x94are elevated two- to three-fold in the cerebrospinal fluid of ALS patients and HCSMA dogs. Additionally, NAALADase activity is significantly increased (two- to three-fold) in post-mortem spinal cord tissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitors might be clinically useful in curbing the progression of ALS if an increased metabolism of NAAG is responsible for the alterations of CSF levels of these acidic amino acids and peptides.
Abnormalities in NAAG levels and NAALADase activity have also been documented in post-mortem schizophrenic brain, specifically in the prefrontal and limbic brain regions.
Applicant inventors have made the surprising and unexpected discovery that NAALADase inhibitors can affect angiogenesis in tissues containing NAALADase. Previous research has shown that NAALADase is enriched in synaptic plasma membranes and is primarily localized to neural and kidney tissue. NAALADase has also been found in the tissues of the prostate and testes. Additionally, previous findings have shown NAALADase to be present in neovasculature. Furthermore, as NAALADase continues to be discovered in other tissues of the body, NAALADase inhibitors most likely will also show efficacy in the inhibition of angiogenesis in those tissues.
While a few NAALADase inhibitors have been identified, they have only been used in non-clinical research. Examples of such inhibitors include general metallopeptidase inhibitors such as o-phenanthroline, metal chelators such as EGTA and EDTA, and peptide analogs such as quisqualic acid and xcex2-NAAG. Accordingly, a need exists for new NAALADase inhibitors, as well as pharmaceutical compositions and methods using such new and known NAALADase inhibitors, to inhibit angiogenesis.
The present invention relates to pharmaceutical compositions comprising:
(i) an anti-angiogenic effective amount of a NAALADase inhibitor; and
(ii) a pharmaceutically acceptable carrier.
The present invention further relates to methods of inhibiting angiogenesis, comprising administering an effective amount of a NAALADase inhibitor to a patient in need thereof.